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CuCN-Mediated O-Alkylation ofN,N,-Dimethylformamide withAlkyl HalidesB. T. S. Thirumamagal a & Sureshbabu Narayanasamya

a Department of Organic Chemistry , University ofMadras , Guindy Campus, Chennai, IndiaPublished online: 14 Jul 2009.

To cite this article: B. T. S. Thirumamagal & Sureshbabu Narayanasamy (2009) CuCN-Mediated O-Alkylation of N,N,-Dimethylformamide with Alkyl Halides, SyntheticCommunications: An International Journal for Rapid Communication of SyntheticOrganic Chemistry, 39:16, 2917-2922, DOI: 10.1080/00397910802696220

To link to this article: http://dx.doi.org/10.1080/00397910802696220

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CuCN-Mediated O-Alkylationof N,N,-Dimethylformamide

with Alkyl Halides

B. T. S. Thirumamagal and Sureshbabu NarayanasamyDepartment of Organic Chemistry, University of Madras,

Guindy Campus, Chennai, India

Abstract: This article reports the CuCN-mediated O-alkylation of formamidewith 2-bromomethylindole. In addition, the formyloxylation products have beensuccessfully exploited in the synthesis of novel indol-2-ylmethyl ether derivatives.

Keywords: O-Alkylation of amides, CuCN, formyloxylation, transition-metalcyanide

INTRODUCTION

The formate esters can be synthesized by O-formylation of alcohols usingvarious formylating agents[1] including Vilsmeier–Haack reagent.[2] Amore compelling alternative method for the synthesis of formate esterderivatives is via an O-alkylation of amides with alkyl halides.[3] Reportsthat exploit dimethylformamide (DMF) as a formate anion equivalent inthe synthesis of formate ester have also been revealed.[4] CuCN is a widelyrenowned transition-metal cyanide in organometallic chemistry that hasvaluable synthetic capabilities[5] and a cascade of catalytic activities.[6]

Herein we propose a method that could effectively make use of CuCNin the O-alkylation of amides with alkyl halides.

Received October 9, 2008.Address correspondence to B. T. S. Thirumamagal, Restorative and Prosthe-

tic, 305 W. 12th Avenue, The Ohio State University, Columbus, OH 43210, USA.E-mail: srinivasaraghava.2@osu.edu

Synthetic Communications1, 39: 2917–2922, 2009

Copyright # Taylor & Francis Group, LLC

ISSN: 0039-7911 print=1532-2432 online

DOI: 10.1080/00397910802696220

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RESULTS AND DISCUSSION

Scheme 1 presents the strategies for the synthesis of the compounds ofinterest. Transition-metal cyanide CuCN was used in the directO-alkylation of DMF with bromo compounds 1 and 2, leading to theformation of formate esters 3 and 4, respectively. Bromo compounds 1

and 2 were prepared sequentially via an allylic bromination of the corre-sponding methyl derivatives[7,8] using N-bromosuccinimide (NBS) in thepresence of a catalytic amount of benzoyl peroxide in dry CCl4 underreflux. Reaction of 1 equiv of bromo compound 1 with 3.5 equiv ofCuCN in dry DMF followed by the conventional workup afforded for-mate ester 3 as a white spongy solid in 65% yield after purification.The 1H NMR spectrum of formate ester 3 displayed O–CO–H andCH2 protons as two singlets at d 8.04 and d 5.8, respectively, besidesthe aromatic protons. CuCN was also efficiently used with the otherbromo compound 2 under the same reaction conditions to afford formateesters 4 in 51% yield after chromatographic purification (SiO2) usinghexanes=ethylacetate 6=4 as the eluting solvent. The utility of CuCN inthe formyloxylation reaction has also been established by a plausiblemechanism, which agrees with previous extensive reports,[9] althoughno intermediates were isolated. The fundamental role of cuprous ionshas also been clearly demonstrated by the fact that the reaction wasunsuccessful in the absence of cuprous cyanide as well as the fact thatthe bromo compounds 1 and 2 are stable in DMF.

Because there is no extensive report on the synthesis of ether deriva-tives 5–9, it was therefore our interest to exploit the formate esters 3 and 4

in the synthesis of the former, which could be used as potential intermedi-ates. The treatment of formate ester 3 in dry chloroform with thionyl

Scheme 1. CuCN-mediated synthesis of indol-2-ylmethylformate ester 3 and 4

and indol-2-ylmethyl ether derivatives 5–9. Reagents and conditions: (i) (a)CuCN, DMF, 25–30�C, 6–10 h; (b) H2O, yield 51–65%; (ii) SOCl2, ROH, CHCl3.0–30�C, 7 h, 60–78%.

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chloride followed by the addition of methanol, ethanol, isobutyl alcohol,and p-cresol at 0–30�C afforded ether derivatives 5–8 respectively in70–78% yield after chromatographic purification (SiO2) using hexanes=ethylacetate (8=2) as the eluting solvent. The 1H NMR spectrum of theether derivative 5 displayed OCH3 and CH2 protons as two singlets atd 3.3 and d 4.6 respectively, in addition to the aromatic protons. Reactionof isobutyl alcohol with other formate ester 4 under the same reactionconditions afforded ether derivative 9 in 60% yield (Scheme 1).

Though it was perceived that CuCN could be principally used in thesynthesis of nitrile derivatives, for the first time our study[10] has demon-strated the utility of CuCN in the formate ester synthesis at roomtemperature, which in turn has opened up an effective means for theformyloxylation reactions because it is simpler than other methods. Inaddition, we also report a synthesis of novel indol-2-ylmethyl etherderivatives.

EXPERIMENTAL

DMF was distilled from calcium hydride and stored over molecularsieves (pore size 3 A). Chloroform was distilled from P2O5 and storedover molecular sieves (pore size 4 A). CuCN was purchased from AldrichChemicals. 1H NMR and 13C NMR spectra were recorded in CDCl3, andtetramethylsilane (TMS) was used as an internal standard. Merck silicagel (ACME, l00–200 mesh) was used for column chromatography. Allthe other reagents were purchased commercially and used as such unlessstated otherwise.

Synthesis of Formate Ester Derivatives: General Procedure

Cuprous cyanide (3.5mmol) was added to a solution of 2-bromomethy-lindole 1 and 2 (1mmol) in dry DMF (10mL) and stirred at 25–30�Cfor 6–10 h. The solution color was changed to green, and the course ofthe reaction was followed by thin-layer chromatography (TLC). Thereaction mixture was poured into crushed ice. The solid obtained wasfiltered and washed meticulously with ethylacetate (30–40mL). The filtratewas extracted further with ethylacetate (3� 20mL) and brine (10mL).Both the organic layers were combined and then dried over anhydrousNa2SO4. Solvent removal followed by the chromatographic (SiO2) purifi-cation and recrystallization (absolute ethanol) of the residues affordedformate esters 3 and 4 in 40–65% yield.

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Spectroscopic Data of Formate Ester Derivatives

Formic acid 1-benzenesulfonyl-3-phenylsulfanyl-1H-indol-2-ylmethyl ester (3)

Yield 65%; mp 140–142�C; IR (KBr) cm�1 1722 (C¼O), 1328, 1163;1H NMR (CDCl3) d 5.8 (s, 2H, CH2), 7.0–8.3 (m, 14H, aromatic), 8.04(s, 1H, O–CO–H); 13C NMR (CDCl3) d 55.8, 103.1, 115.4, 120.0,121.2, 122.1, 125.3, 126.5, 127.4, 128.2, 129.3, 129.1, 132.6, 134.1,135.0, 138.5, 140.5, 165.0 m=z: 423 (Mþ). Anal. calcd. for C22H17NO4S2:C, 62.39, H, 4.05; N, 3.31. Found: C, 62.09; H, 4.13; N, 3.11.

Formic acid 1-benzenesulfonyl-3-chloro-1H-indol-2-ylmethyl ester (4)

Yield 51%; mp 130–133�C; IR (KBr) cm�1 1726 (C¼O), 1331, 1160;1H NMR (CDCl3) d 5.5 (s, 2H, CH2), 7.2–7.9 (m, 9H, aromatic), 8.1(s, 1H, O–CO–H); 13C NMR (CDCl3) d 56.3, 114.1, 120.2, 121.5,125.8, 126.4, 127.7, 128.0, 129.5, 130.8, 134.4, 138.5, 139.9, 165.0 m=z:349 (Mþ), 351 (Mþ 2). Anal. calcd. for C16H12ClNO4S: C, 54.94; H,3.46; N, 4.00. Found: C, 54.88; H, 3.73; N, 4.12.

Synthesis of Ether Derivatives: General Procedure

Thionyl chloride (0.5mL) was added to a solution of indol-2-ylmethylfor-mate esters 3 and 4 (1mmol) in dry chloroform (10mL) and stirred at 0�Cfor 1 h. Further alcohol (5mL) was added and stirred at 30�C for 6 h. Thecourse of the reaction was followed by TLC. The excess alcohol wasremoved, and the reaction mixture was poured into crushed ice andextracted with chloroform (3� 30mL). The chloroform layer was driedover anhydrous Na2SO4 and filtered. Solvent removal followed by thechromatographic (SiO2) purification of the residue using hexanes=ethylacetate (8=2) as the eluting solvent afforded indol-2-ylmethyl etherderivatives 5–9.

Spectroscopic Data of Ether Derivatives

1-Benzenesulfonyl-2-methoxymethyl-3-phenylsulfanyl-1H-indole (5)

Viscous liquid; 75% yield; IR (KBr) cm�1 1318, 1167, 1143; 1H NMR(CDCl3) d 3.3 (s, 3H, CH3), 4.6 (s, 2H, CH2), 7.2–7.9 (m, 14H, aromatic);

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13C NMR (CDCl3) d 58.8, 66.1, 115.4, 118.0, 120.5, 125.2, 127.0, 127.1,127.5, 128.7, 129.2, 129.3, 130.4, 130.9, 134.0, 134.4, 138.5, 141.0; m=z:409 (Mþ). Anal. calcd. for C22H19NO3S2: C, 64.52; H, 4.68; N, 3.42.Found: C, 64.43; H, 4.53; N, 3.37.

1-Benzenesulfonyl-2-ethoxymethyl-3-phenylsulfanyl-1H-indole (6)

Viscous liquid; 78% yield; IR (KBr) cm�1 1320, 1170, 1150; 1H NMR(CDCl3) d 1.09–1.12 (t, J¼ 7.1Hz, 3H, OCH2CH3), 3.3–3.4 (q, J¼ 7.6Hz,2H, OCH2), 4.7 (s, 2H, CH2O), 7.2–7.8 (m, 14H, aromatic); 13C NMR(CDCl3) d 14.8, 65.7, 66.9, 114.1, 118.7, 120.0, 125.2, 126.1, 127.0,127.5, 128.4, 129.2, 129.3, 129.4, 130.4, 134.0, 134.3, 138.5, 140.7; m=z423 (Mþ). Anal. calcd. for C23H21NO3S2: C, 65.22; H, 5.00; N, 3.31.Found: C, 65.52; H, 4.73; N, 3.23.

1-Benzenesulfonyl-2-isobutoxymethyl-3-phenylsulfanyl-1H-indole (7)

Viscous liquid; 70% yield; IR (KBr) cm�1 1329, 1161, 1148; 1H NMR(CDCl3) d 0.95 [d, J¼ 6.9Hz, 6H, (CH3)2], 1.8–1.9 (m, 1H, CH), 3.2(d, J¼ 7.0Hz, 2H, OCH2), 4.6 (s, 2H, CH2O), 7.2–7.9 (m, 14H, aro-matic); 13C NMR (CDCl3) d 20.0, 29.1, 65.8, 76.2, 114.3, 118.0, 120.5,125.3, 126.9, 127.0, 128.9, 129.1, 129.2, 129.5, 130.4, 131.0, 134.0,134.4, 138.5, 140.7; m=z: 451 (Mþ). Anal. calcd. for C25H25NO3S2: C,66.49; H, 5.58; N, 3.10. Found: C, 66.32; H, 5.23; N, 2.98.

1-Benzenesulfonyl-3-phenylsulfanyl-2-p-tolyloxymethyl-1H-indole (8)

Mp 130–132�C; 72% yield; IR (KBr) cm�1 1321, 1180, 1153; 1H NMR(CDCl3) d 2.2 (s, 3H, CH3), 5.3 (s, 2H, CH2), 6.8–7.8 (m, 18H, aromatic);13C NMR (CDCl3) d 21.0, 65.2, 107.6, 116.2, 118.0, 120.5, 125.2, 125.7,126.1, 126.7, 127.1, 127.8, 128.0, 128.3, 129.0, 129.4, 130.1, 131.6, 134.1,135.0, 138.5, 141.0, 156.0; m=z 485 (Mþ). Anal. calcd. for C28H23NO3S2:C, 69.25; H, 4.77; N, 2.88. Found: C, 69.02; H, 4.67; N, 2.35.

ACKNOWLEDGMENTS

B. T. S. T. acknowledges the University Grants Commission (UGC)–Special Assistance Programme (SAP) for instrument grants to the depart-ment and the University of Madras for a University Research Fund(URF).

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REFERENCES

1. Olah, G. A.; Ohannesian, L. Formylating agents. Chem. Rev. 1987, 87, 671.2. Kotlyar, V.; Shahar, L.; Lellouche, J.-P. A simple homemade reaction station

for use in parallel solution-phase synthesis: Optimization of a regioselectiveone-step deprotective O-formylation reaction mediated by the Vilsmeier–Haack reagent POCl3�bul�DMF. Mol. Divers. 2006, 10, 255.

3. Dakanali, M.; Tsikalas, G. K.; Krautscheid, H.; Katerinopoulos, H. E.Formate ester synthesis via reaction of 2-bromoethylamines with dimethyl-formamide. Tetrahedron Lett. 2008, 49, 1648.

4. (a) Suri, S. C.; Rodgers, S. L.; Radhakrishnan, K. V.; Nair, V. DMF as aformate anion equivalent: Formolysis of tosylates in aqueous DMF. Synth.Commun. 1996, 26, 1031; (b) Lidia, D. L.; Giampaolo, G.; Andrea, P. Mildand highly selective formyl protection of primary hydroxyl groups. J. Org.Chem. 2002, 67, 5152.

5. (a) Doerr, A. A.; Lubell, W. D. Homoallylic ketones and pyrroles by way ofcopper-catalyzed cascade additions of alkyl-substituted vinyl Grignardreagents to esters. Can. J. Chem. 2007, 85, 1006; (b) Misir, M.; Nedim, K.H.; Gok, Y.; Misir, G. Synthesis and characterization of new copperphthalocyanine carrying mixed donor macrocyclic moieties. J. Coord. Chem.2006, 59, 1667.

6. (a) Oestreich, M.; Weiner, B. Copper-catalyzed conjugate addition of abis(triorganosilyl) zinc and a methyl(triorganosilyl) magnesium. Synlett2004, 12, 2139; (b) Arrayas, R. G.; Cabrera, S.; Carretero, J. C. Copper-catalyzed anti-stereocontrolled ring-opening of azabicyclic alkenes withGrignard reagents. Org. Lett. 2005, 7, 219.

7. Sundberg, R. J.; Russel, H. F. Syntheses with N-protected 2-lithioindoles. J.Org. Chem. 1973, 38, 3324.

8. Powers, J. C. Chloroindoles. J. Org. Chem. 1966, 31, 2627.9. (a) Brace, N. O. Amides as nucleophiles: Reaction of alkyl halides with

amides or with amides and water: A new look at an old reaction. J. Org.Chem. 1993, 58, 1804; (b) Antonio, A.; Consuelo, A.; Ana, C. C.; Ismael,N. Conversion of alkyl halides into alcohols via formyloxylation reactionwith DMF catalyzed by silver salts. Synthesis 2005, 19, 3355.

10. Thirumamagal, B. T. S. PhD thesis, University of Madras, 2002.

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